Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that may cause significant impairment in childhood and later life. Symptoms of ADHD include inattentiveness, hyperactivity, and impulsivity.
We previously conducted a large-scale, genome-wide study comparing copy number variations (CNVs) in about 3500 ADHD cases compared to about 13,000 controls, and found that CNVs in genes coding for metabotropic glutamate receptors (mGluR proteins or GRM genes) as well as CNVs in genes coding for proteins that interact with mGluRs occur significantly more frequently in ADHD cases compared to controls. (See WO 2012/027491 and US 2013/0203814; Elia et al., Nature Genetics, 44(1): 78-84 (2012).) The frequency of each individual genetic alteration appears to be quite rare. But collectively, about 11% or more of ADHD cases compared to about 1% of controls have at least one genetic alteration in a gene coding for an mGluR network protein. Thus, ADHD patients are about 10 times more likely than control individuals to have a genetic alteration affecting one or more mGluR network genes. Furthermore, a network analysis of the mGluR pathway in the European American population of approximately 1000 cases and 4000 controls showed that copy number variations (CNVs) in genes coding for proteins involved in mGluR signaling pathways and their interacting proteins impact about 20% of ADHD cases compared to controls.
There is no cure for ADHD, but the symptoms can be managed by combinations of behavior therapy and medications. Currently approved therapeutics for ADHD include several stimulant and non-stimulant drugs. Current medications are not ideal, especially stimulants, because they have a number of possibly harmful side effects and have short half-lives of activity. Moreover, stimulants are often misused and abused by qualifying and non-qualifying patients alike. Hence, additional ADHD medications are needed. In addition, given the genetic heterogeneity of ADHD patients, tailoring certain medication schemes to patients based on their underlying genetic profile may also improve ADHD treatment.
The inventors have conducted a clinical trial testing a nonselective activator of mGluR proteins called NFC-1 or fasoracetam monohydrate in pediatric ADHD patients who have at least one genetic alteration in a gene coding for an mGluR network protein.
This trial also included ADHD patients who have 22q syndromes, which are characterized by either a deletion (22q deletion syndrome) or duplication (22q duplication syndrome) in the 22q11.2 region of chromosome 22. Those syndromes may occur in at least about 1 out of every 2000-4000 children and may involve disruptions in as many as 30-40 genes. Among the genes that may be affected is RANBP1, an mGluR network gene. Children with a deletion or duplication at 22q11.2 have a higher than average rate of psychiatric disorders including ADHD, autism spectrum (ASD), and anxiety disorder, and a significant percentage may develop psychoses such as schizophrenia later in life. Children with a deletion or duplication of that region may also suffer from various intellectual disabilities.
Treatment of psychiatric symptoms in 22q syndrome patients may be complicated due to the physical abnormalities of these patients, including cardiac anomalies. For example, it may be necessary to avoid use of otherwise widely-prescribed stimulant drugs due to their negative side effects in the 22q syndrome population. Thus, improved therapeutic treatments are particularly needed for patients with ADHD, ASD, anxiety disorder or other conditions who have an underlying 22q genetic syndrome.